Operationally Simple and Efficient Workup Procedure for TBAF-Mediated Desilylation: Application to Halichondrin Synthesis

An operationally simple and efficient workup method for tetrabutylammonium fluoride (TBAF)-mediated t-butyldimethylsilyl (TBS) deprotection has been developed. The procedure includes addition of a sulfonic acid resin and calcium carbonate, followed by filtration and evaporation. This method eliminates the tedious aqueous-phase extraction process to remove excess TBAF and materials derived from TBAF, thereby making the protocol highly amenable to multiple TBS deprotections. Its efficiency and usefulness were demonstrated by using the transformation of 1a to 3a in the halichondrin synthesis

Total Synthesis of (−)-Strychnine

Total synthesis of (−)-strychnine is described. Notable features of our synthesis include (1) palladium-catalyzed coupling of the indole and vinyl epoxide moieties, (2) synthesis of the nine-membered cyclic amine derivative from the diol precursor in a one-pot procedure, and (3) transannular cyclization of the nine-membered cyclic amine

Total Synthesis of Leustroducsin B

A convergent total synthesis of leustroducsin B (1), which is known to exhibit a variety of biological activities, was successfully carried out. Notable features of our synthesis include construction of the C8 stereocenter by lipase-mediated desymmetrization of meso-diol 4 (90.2% ee) and preparation of the C9−C11 anti-diol moiety by the addition of alkynylzinc reagent 20 to the aldehyde 19. Furthermore, a new diol protecting group, p-silyloxybenzylidene, was developed for the deprotection from densely functionalized substrates under weakly acidic conditions. The protecting group was easily removed in a two-step procedure ((HF)3·Et3N; AcOH−THF−H2O)

Radical Cyclization of 2-Alkenylthioanilides: A Novel Synthesis of 2,3-Disubstituted Indoles

Radical Cyclization of 2-Alkenylthioanilides:  A Novel Synthesis of 2,3-Disubstituted Indole

Radical Cyclization of 2-Alkenylthioanilides: A Novel Synthesis of 2,3-Disubstituted Indoles

Radical Cyclization of 2-Alkenylthioanilides:  A Novel Synthesis of 2,3-Disubstituted Indole

New Syntheses of E7389 C14−C35 and Halichondrin C14−C38 Building Blocks: Reductive Cyclization and Oxy-Michael Cyclization Approaches

Cr-mediated coupling reactions are usually achieved with a slight excess of a given nucleophile. To develop a cost-effective use of this process, two different approaches have been studied. The first approach depends on two consecutive catalytic asymmetric Cr-mediated couplings, with use of coupling partners purposely being of unbalanced molecular size and complexity. The second approach rests on the success in identifying the nucleophile, which allows us to achieve the coupling satisfactorily with a 1:1 molar ratio of the coupling partners. The C23−O bond is stereospecifically constructed via reductive cyclization of the oxonium ion, or oxy-Michael cyclization. Both syntheses have a high overall efficiency: E7389 C14−C35 and halichondrin C14−C38 building blocks have been synthesized from the corresponding C27−C35 and C27−C38 aldehydes, respectively, in high overall yields with an excellent stereoselectivity. Because of operational simplicity, the synthesis outlined herein appears to be well suited for scaling

Ten-Gram-Scale Total Synthesis of the Anticancer Drug Candidate E7130 to Supply Clinical Trials

E7130 is a novel drug candidate with an exceedingly complex chemical structure of the halichondrin class, discovered by a total synthesis approach through joint research between the Kishi group at Harvard University and Eisai. Only 18 months after completion of the initial milligram-scale synthesis, ten-gram-scale synthesis of E7130 was achieved, providing the first good manufacturing practice (GMP) batch to supply clinical trials. This paper highlights the challenges in developing ten-gram-scale synthesis from the milligram-scale synthesis